We have shown that patients with essential hypertension have a reduced endothelium-dependent vascular response to substance P. We have also shown that the endothelial dysfunction of hypertensive patients is related to a defect at the level of the nitric oxide system. However, the contribution of nitric oxide to endothelium-dependent vasodilation to substance P has not been investigated in humans. To address this issue, we studied the response to substance P before and after administration of NG-monomethyl-L-arginine (L-NMMA) in 8 hypertensive patients and 8 normal controls. L-NMMA is an arginine analogue that competitively inhibits the synthesis of nitric oxide by the endothelium. Thus, the use of this substance permits the study of the nitric oxide system in the physiologic and pathophysiologic regulation of vascular tone. Drugs were infused into the brachial artery and the forearm blood flow was measured by strain gauge plethysmography. As shown before, the vasodilator response to substance P was significantly depressed in hypertensive patients compared to normal controls. L-NMMA significantly blunted the response to substance P in normals and in hypertensive patients. However, the magnitude of inhibition of the response to substance P by L-NMMA was significantly greater in the normal controls. Therefore, when the response to substance P after infusion of L-NMMA was compared, there was no difference between patients and normals. Thus, these findings indicate the vasodilator effect of substance P in humans is at least partly mediated by the release of endothelium-derived nitric oxide. The equalization of the response to substance P after administration of L-NMMA and therefore inhibition of nitric oxide synthesis indicates that the impaired response to substance P of hypertensive patients is related to a defect in endothelial synthesis or release of nitric oxide.